The spatial separation of DNA replication and gene transcription in the nucleus and protein translation in the cytoplasm is a uniform principle of eukaryotic cells. This compartmentalization imposes a requirement for a transport network of macromolecules to shuttle these components in and out of the nucleus. This nucleo-cytoplasmic transport of macromolecules is critical for both cell physiology and pathology. Consequently, investigating its regulation and disease-associated alterations can reveal novel therapeutic approaches to fight human diseases, such as cancer or viral infection. The characterization of the nuclear pore complex, the identification of transport signals and transport receptors, as well as the characterization of the Ran system (providing the energy source for efficient cargo transport) has greatly facilitated our understanding of the components, mechanisms and regulation of the nucleo-cytoplasmic transport of proteins in our cells. Here we review this knowledge with a specific emphasis on the selection of disease-relevant molecular targets for potential therapeutic intervention.

No abstract

The human multidrug resistance gene MDR3 encodes a P-glycoprotein that belongs to the ATP-binding cassette transporter family (ABCB4). MDR3 is a critical trans-locator for phospholipids across canalicular membranes of hepatocytes, evidenced by the fact that human MDR3 deficiencies result in progressive familial intrahepatic cholestasis type III. It has been reported previously that MDR3 expression is modulated by hormones, cellular stress, and xenobiotics. Here we show that the MDR3 gene is trans-activated by the farnesoid X receptor (FXR) via a direct binding of FXR/retinoid X receptor ␣ heterodimers to a highly conserved inverted repeat element (a FXR response element) at the distal promoter (؊1970 to ؊1958). In FXR trans-activation assays, both the endogenous FXR agonist chenodeoxycholate and the synthetic agonist GW4064 activated the MDR3 promoter. Deletion or mutation of this inverted repeat element abolished FXR-mediated MDR3 promoter activation. Consistent with these data, MDR3 mRNA was significantly induced by both chenodeoxycholate and GW4064 in primary human hepatocytes in time-and dose-dependent fashions.In conclusion, we demonstrate that MDR3 expression is directly up-regulated by FXR. These results, together with the previous report that the bile salt export pump is a direct FXR target, suggest that FXR coordinately controls secretion of bile salts and phospholipids. Results of this study further support the notion that FXR is a master regulator of lipid metabolism.ATP-binding cassette (ABC) 1 transporters constitute a large family of proteins, and many have been shown to be involved in lipid transport. MDR3 (ABCB4), a P-glycoprotein, is predominantly expressed in the liver (1) and is the critical trans-locator for phospholipids across canalicular membranes of hepatocytes (2). The MDR3 function is essential for the liver as evidenced by the fact that MDR3 deficiencies in humans result in progressive familial intrahepatic cholestasis type III (3,4). A number of factors, such as hormones, cellular stress, and xenobiotics have been shown to modulate MDR3 expression (5-7). However, the underlying molecular mechanisms for MDR3 gene regulation are unclear. In this study, we demonstrate that the bile acid receptor FXR directly regulates expression of MDR3.FXR is a nuclear receptor for bile acids and regulates expression of a number of genes in which products are critically important for bile acid and cholesterol homeostasis (8 -11). FXR functions as a heterodimer with the 9-cis-retinoic acid receptor (RXR␣) (12, 13), and the FXR/RXR␣ heterodimer activates gene transcription via binding to a specific DNA sequence comprised of two inverted hexamer repeats separated by one nucleotide (IR-1) in the target promoter. To date, there is only one reported case in which FXR down-regulates apolipoprotein A-I expression via a FXR monomer or homodimer binding to an .Previous studies (15, 16) have shown that agonist-bound FXR directly regulates expression of the bile salt export pump (BSEP), an ABC transporter (ABCB11) ...

The purpose of the present study was to characterize daily variations in haematology and blood biochemistry in healthy male and female tench (Tinca tinca) in the four seasons of the year. Red blood cells, haematocrit and haemoglobin presented a similar daily pro-¢le in spring and summer, with high values during the scotophase. Total and di¡erential types of leucocytes showed signi¢cant daily £uctuations, with a di¡erent pattern depending on the season and/or the type of leucocytes studied. A daily rhythm in plasma glucose and triglycerides was detected in winter, but signi¢cant changes in cholesterol concentrations were only detected in females during summer. The lowest mean level for triglycerides and cholesterol was observed in winter. The daily pro¢le of plasma total proteins was similar in the four seasons, without a signi¢cant daily oscillation. All these daily and seasonal changes in haematology and blood biochemistry indicate that the time of the day and the season must be considered when such parameters are used for assessing the physiological status of the ¢sh, and as biomarkers for disease and/or pollutant exposure.

The purpose of the present study was to elucidate the possible role of leptin in food intake and body weight regulation in goldfish. We examined the effects of i.c.v. or i.p. acute leptin administration on food intake in fooddeprived goldfish at different time intervals post-injection (0-2, 2-8 and 0-8 h). Food intake was reduced by i.p. administered leptin (1 µg) at 8 h post-injection, without statistically significant differences after i.c.v. treatment. The present study shows for the first time in a teleost that chronic (10 days) leptin treatment (i.p.) reduces food intake, body weight gain, specific growth rate and food efficiency ratio. Moreover, lipid and carbohydrate metabolism seems to be regulated by leptin in fish.Chronic leptin treatment increased lipid mobilization and carbohydrate storage as hepatic and muscle glycogen. Finally, leptin could mediate its actions on energy homeostasis in fish, at least in part, through interactions with hypothalamic catecholamines, since chronic leptin treatment reduced both hypothalamic noradrenergic and dopaminergic turnover without significant modifications in hypothalamic serotoninergic and neuropeptide Y (NPY) systems. In summary, our results suggest that leptin can regulate feeding behaviour and body weight homeostasis in fish.